Quantitative effects on gene silencing by allelic variation at a tetranucleotide microsatellite

Microsatellites are common repeated sequences, which are useful as genetic markers and lack any clearly established function. In a previous study we s uggested that an intronic polymorphic TCAT repeat in the tyrosine hydroxyla se (TH) gene, the microsatellite HUMTH01, may regulate transcription. The T H gene encodes the rate-limiting enzyme in the synthesis of catecholamines, and the microsatellite HUMTH01 has been used in genetic studies of neurops ychiatric and cardiovascular diseases, in which disturbances of catecholami nergic neurotransmission have been implicated. HUMTH01 alleles associated w ith these diseases act as transcriptional enhancers when linked to a minima l promoter and are recognized by specific nuclear factors. Here we show tha t allelic variations of HUMTH01 commonly found in humans have a quantitativ e silencing effect on TH gene expression. Two specific proteins, ZNF191, a zinc finger protein, and HBP1, an HMG box transcription factor, which bind the TCAT motif, were then cloned. Finally, allelic variations of HUMTH01 co rrelate with quantitative and qualitative changes in the binding by ZNF191. Thus, this repeated sequence may contribute to the control of expression o f quantitative genetic traits. As the HUMTH01 core motif is ubiquitous in t he genome, this phenomenon may be relevant to the quantitative expression o f many genes in addition to TH.